Development of ELQ300 as a long acting antimalarial
Project Completed
Please click to see the final report.
  • Awarded Year
    2013
  • Awarded Amount
    $560,000
  • Disease
    Malaria
  • Intervention
    Drug
  • Development Stage
    Preclinical development
  • Collaboration Partners
    Takeda Pharmaceutical Company Limited, Medicines for Malaria Venture (MMV)

Introduction and Background of the Project

ELQ-300 is an approved preclinical candidate in the portfolio of Medicines for Malaria Venture. ELQ-300 has enormous potential as an antimalarial for treatment and prophylaxis, given its excellent parasitological profile (with the potential for low-dose cures or low single-dose prophylaxis and transmission blocking). However, the compound has low solubility and formulation work is required to deliver a developable medicine with sufficient exposure in GLP (Good Laboratory Practices) safety studies and, ultimately, in the clinic.

How can your partnership (project) address global health challenges?

The top priority for malaria treatment is to provide the next generation of medicines, which can either support single exposure radical cure and prophylaxis, or ensure chemoprotection.

Ultimately it would be better to prevent the population becoming infected rather than treating the patients once they become symptomatic. Contrary to other diseases, where protection has been achieved with vaccination, malaria prevention and control has relied on chemoprotection since the earliest days of quinine therapy. Anti-malarial drugs target different stages of the parasites lifecycles. In general, they must be safe enough for use in sensitive populations such as pregnant women, the youngest of children and patients with other morbidities, such as HIV, Tuberculosis (TB), and/or malnutrition.

The current gold standards for chemoprophylaxis are atovaquone-proguanil and mefloquine, which are both far from ideal.

ELQ300 has been shown to be a long-duration compound, with a potential to be a ‘new’ atovaquone superior in terms of, resistance frequency. ELQ-300 is expected to be a compelling partner for use in curative combinations and chemoprotection, with a reasonable longevity in the field.

The frequency with which a chemoprophylactic has to be delivered is critical. A chemoprophylactic should maintain its plasma concentration above the minimal parasiticidal concentration for an extended period of time, preferably supporting a once-per-month regimen. It also needs to be extremely well tolerated, considering that it will be given primarily to healthy individuals. Finally, it should be a different class of molecule from those used in treatment of malaria in the country in which it is deployed, in order to minimize the threat of cross resistance with therapeutic regimens.

The development of ELQ300 is designed to address the challenge of chemoprotection and to support elimination and eradication.

What sort of innovation are you bringing in your project?

Medicines for Malaria Venture and Takeda Pharmaceuticals propose to collaborate to solve the formulation issue. Takeda possess CMC (Chemistry, Manufacturing, and Control) expertise and capabilities at the highest industrial level. Merging this expertise with that of MMV would provide an excellent synergy to solve this critical issue.

Whilst this partnership is focused on a single workstream, the reformulation of the compound, it could be expanded in the future to include subsequent steps (i.e. GLP safety studies etc.), and could potentially form the basis for a longer-term partnership for the development and commercialization of ELQ-300 within a Japanese regulatory context.

ELQ-300 is a long-duration antimalarial currently positioned as a chemoprophylactic agent. The compound possesses a similar mechanism of action of atovaquone, a marketed chemoprophylactic agent to which resistance rapidly developed. ELQ-300 is active against atovaquone-resistant strains. Hence, in addition to its potential for long duration of coverage (ideal profile for chemoprotection), and it has a reduced resistance risk. ELQ300 could also have potential for single-dose treatment of malaria in combination with a fast-acting partner.

ELQ300 entered preclinical development in Q3 2012. The principal risks are associated with its very low solubility in aqueous and biorelevant media, which has hampered absorption in high doses in vivo DMPK (Distribution Metabolism and PharmacoKinetics) experiments and achievement of adequate levels of exposure to demonstrate therapeutic margins. The proposed partnership will enable extensive formulation work which, coupled with a standard preclinical development package, should allow establishment of a safety margin and progression into man.

Specifically, the areas to still be explored include lipid-based formulations, co-solvents, and amorphous dispersions. Frontrunner formulations would then be tested in rodents and dogs to confirm increased exposure of drug necessary for safety studies and further development.

Final Report

1. Project objective

In light of the growing drug resistance to malaria, new compounds to fight this deadly disease are urgently needed. Under this project, MMV and Takeda have collaborated to try to solve a challenging formulation issue for ELQ300 using Takeda’s Chemistry, Manufacturing and Controls expertise in solid oral dosage form development. The objective was to deliver a clinically acceptable formulation of ELQ300.

 

2. Project design 

The main objective was to deliver of a clinically acceptable formulation that achieves sufficient exposure to define a safety margin and continue formal preclinical and clinical development. If this was confirmed, progress to kilo production.

 

3. Results, lessons learned 

The ELQ300 project was stopped during the year of 2014, as a result of it being clear that a suitable formulation with increased plasma exposure of the compound could not be found. The formulations identified during the duration of the project as potential hits to increase bioavailability did not meet the criteria set by the project team (i.e. BA > 20%), and the No Go decision was reached. Hence the project was terminated. Enabling formulations, such as nanosuspensions, and lipid-based formulations are a great tool often used in Pharmaceutical Development to overcome shortcomings such as solubility, and/or dissolution-limited absorption. Nonetheless, the cost of goods, and ultimately the cost of treatment is a crucial aspect for drug products intended for under developed or developing countries. Drug products for malaria treatment need to be affordable, and MMV goal remains to have the cost per treatment below 1 USD. This needs to be taken into account when developing enabling formulations which could increase drastically the overall cost of treatment GHIT Fund awarded MMV with JPY 56,000,000. However, due to an unspent amount of JPY 34,320,945 at the end of the project, MMV refunded this total to the GHIT Fund as per its grant agreement.